EP0777451B1 - Ophthalmologisches abgabesystem - Google Patents

Ophthalmologisches abgabesystem Download PDF

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Publication number
EP0777451B1
EP0777451B1 EP95923983A EP95923983A EP0777451B1 EP 0777451 B1 EP0777451 B1 EP 0777451B1 EP 95923983 A EP95923983 A EP 95923983A EP 95923983 A EP95923983 A EP 95923983A EP 0777451 B1 EP0777451 B1 EP 0777451B1
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EP
European Patent Office
Prior art keywords
pilocarpine
sodium alginate
eye
ophthalmic formulation
formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP95923983A
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English (en)
French (fr)
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EP0777451A1 (de
EP0777451A4 (de
Inventor
Smadar Cohen
Esther Lobel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Ben Gurion University of the Negev BGU
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Teva Pharmaceutical Industries Ltd
Ben Gurion University of the Negev BGU
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Publication of EP0777451A4 publication Critical patent/EP0777451A4/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the present invention relates to a novel delayed release composition suitable for the release of active ingredients to a human or animal body, and especially well suited for the release of active ingredients via the ocular route.
  • Eye ointments may increase the residence time of ocular drugs but they are inconvenient to use, impair the vision by blurring and are therefore generally only recommended to be administered prior to going to sleep.
  • Liquid vehicles for delivery of active ingredients to the eye have also been suggested.
  • liquid vehicles generally suffer from the disadvantage that a large proportion of the liquid vehicle and hence the active agent administered is lost as a result of lacrimal drainage because the site of delivery to the eye is both fluid and mobile.
  • phase transition systems to deliver ophthalmic drugs at a controlled rate.
  • phase transition systems may be applied to the eye in a liquid form and only once in the culs-de-sac will they shift to their gel phase.
  • phase transfer systems have been reported.
  • Poloxamer 407 described in Miller SC et al., (1982) Int J Pharm 12 147-152
  • solution viscosity increases when its temperature is raised to the eye temperature.
  • CAP cellulose acetophthalate
  • the polymer coagulates when its native pH of 4.5 is raised by the tear fluid to pH 7.4.
  • Both systems are characterized by a high polymer concentration (25% Poloxamer, 30% CAP) which is not well tolerated by the eye.
  • the surfactive properties of the former and the low pH of the latter may be detrimental to ocular tolerance.
  • GelriteTM a polysaccharide which forms clear gels in the presence of mono or divalent cations described in Moorhouse R et al. (1981) In “Solution Properties of Polysaccharides” pages 111-124 Ed. Brandt DA, Washington DC.
  • this polymer changes from the liquid phase to the gel phase as a result of the ionic strength of the lacrimal fluid. Because it can form gels at low concentrations ( ⁇ 0.6% w/w), it is well tolerated by the eye.
  • GelriteTM One of the disadvantages of GelriteTM is the incompatibility of GelriteTM solutions with ionised formulation ingredients such as buffers, as the GelriteTM solution will undergo premature phase transition. Therefore potential ion pair-forming agents have to be added and the total ionic strength of the formulation must be kept low.
  • Alginate is a block-copolymer containing two kinds of homopolymeric blocks, of ⁇ -D mannuronic acid (M-M) blocks and ⁇ -L-guluronic acid (G-G) blocks together with blocks with alternating sequence (M-G).
  • M-M ⁇ -D mannuronic acid
  • G-G ⁇ -L-guluronic acid
  • M-G alternating sequence
  • compositions for the treatment of the human eye which are formed by combining at least two components capable of gel formation with one another.
  • One of the components may be an alginate and the other component is preferably a calcium salt.
  • the composition may optionally additionally contain a therapeutic ingredient.
  • the two components capable of gel formation are dissolved separately from one another.
  • the individual solutions are then applied successively or simultaneously to the eye whereupon gelation occurs and the resultant gel adheres to the eye, keeping it moist and also enabling drugs to be applied with lower frequency.
  • the present invention advantageously provides a delivery formulation suitable for extending the duration of activity of an active agent administered to the eye.
  • the present invention includes a formulation comprising a therapeutically effective amount of at least one active agent together with an alginate whose composition comprises at least 50% guluronic acid.
  • the formulation Prior to application to the eye, the formulation is preferably substantially non-gelled. After application to the eye and exposure to the lacrimal fluid, it is preferred that the formulation gel to an extent sufficient to maintain the presence of the therapeutically active agent in the ocular region.
  • the formulations of the present invention advantageously maintain the presence of an active agent in the eye, thus extending the effect of such active agent and reducing the frequency of drug administration. They are also easy to administer and are more comfortable to the user than many prior art formulations.
  • the formulations of the present invention comprise an alginate wherein the guluronic acid content is at least 50%, preferably at least 60%, more preferably at least 70%, and a therapeutically active agent.
  • the formulations of the present invention may alternatively be defined in terms of the proportion of mannuronic acid in the alginate.
  • the present invention also relates to a controlled release formulation comprising a therapeutically effective amount of at least one active agent together with an alginate whose composition comprises no more than 50% mannuronic acid.
  • the alginate comprises no more than 40% mannuronic acid, more preferably no more than 30% mannuronic acid.
  • the alginate utilized in the formulations of the present invention comprises from 50-95% guluronic acid and from 5-50% mannuronic acid
  • the formulations of the present invention are substantially non-gelled prior to contact with lacrimal fluid.
  • the therapeutically active agent, and the alginate are preferably dissolved and/or suspended in a pharmacologically safe solution prior to application.
  • alginate may be utilized in the solution, together with the active agent, to permit the formulation to sufficiently gel upon contact with lacrimal fluid.
  • Suitable pharmacologically safe solutions include, but are not limited to the following: preservatives, tonicity agents, buffers as known in the art, or water for injection.
  • formulations of the present invention are particularly advantageous when used to delivery therapeutic agents to the eye.
  • Therapeutic agents that are suitable for inclusion in the formulations of the present invention for opthalmic administration include, but are not limited to: glaucoma agents such as beta-adrenergic blockers such as timolol, betaxolol, levobunolol, metipranolol and carteolol; adrenergic agonists such as epinephrine, apraclonidine and related 2-substituted amino imidazolines; carbonic anhydrase inhibitors such as acetazolamide, methazolamide and aryl and heteroaryl sulphonamides; miotic cholinergic drugs such as pilocarpine and carbachol; dopamine agonists and antagonists; alpha-2 adrenergic agonists; anti-inflammatory agents, non-steroids such as diclofenac and ketorolac and steroids including, prednisolone acetate, tetrahydrocortisol; methotrexate and
  • the formulations of the present invention may contain up to 50% of active agent, preferably 0.25-10% (w/v).
  • active agent preferably 0.25-10% (w/v).
  • the necessary amount of formulation to administer can then be calculated by the man skilled in the art.
  • the formulations of the present invention may also be utilized in the absence of an active agent to treat conditions such as dry eye.
  • the formulations of the present invention are also useful without a therapeutic agent for preventing dryness of the eye, a condition associated with dry eye syndrome.
  • the formulations of the present invention are also useful in the treatment or prevention of other conditions of the eye associated with aging, smog, sport, systemic medication, clinical conditions such as Sjorgen's Syndrome, chemotherapy, collagen diseases or malnutrition.
  • the present invention further relates to a method of treating diseases of the eye comprising administering an alginate whose composition comprises at least 50% guluronic acid.
  • the formulations of the present invention may optionally further contain other ophthalmically acceptable agents including buffers, disinfectants, preservatives such as Thimerosal, chlorobutanol or paraben or tonicity agents such as sodium chloride and mannitol.
  • ophthalmically acceptable agents including buffers, disinfectants, preservatives such as Thimerosal, chlorobutanol or paraben or tonicity agents such as sodium chloride and mannitol.
  • the rabbits were divided into two groups.
  • the IOP was measured in both eyes of each rabbit at various times during the 24 hours prior to drug administration using topically applied local anesthetic (Benoxinate 0.4% Fischer Co.) to obtain a baseline reading.
  • topically applied local anesthetic Benoxinate 0.4% Fischer Co.
  • the alginates utilized were as follows: Alginate % guluronic acid % mannuronic acid Source Ag1 40-50 50-60 LF200B Ag2 65-70 30-35 MANUGEL DMB Ag3 35-40 60-65 KELTONE LV Ag4 65-75 25-35 SF120 LF200B alginate and SF120 alginate were both obtained from Pronova Biopolymer. MANUGEL DMB alginate and KELTONE LV alginate were both obtained from Kelco International, Waterford, Tadworth, Surrey KT20 5HQ, United Kingdom.
  • a drop of each pilocarpine/alginate formulation was administered to one eye of each rabbit in the second treatment group.
  • the pilocarpine percentage of the formulation is shown in Table 1 below.
  • Figure 1 shows intraocular pressure (IOP) before and after treatment with pilocarpine and pilocarpine in combination with 1% Ag1, an alginate having a guluronic acid percentage below that specified for the alginate formulations used in the present invention.
  • Figure 1 depicts the mean baseline values for six rabbits, for pilocarpine (without carrier) and mean baseline values for six rabbits, for the Ag1 formulation without pilocarpine.
  • the term baseline is utilized to the series of IOP measurements taken at specified time intervals.
  • Figure 1 also depicts the mean values of IOP for six rabbits after treatment with a 2% pilocarpine solution and the formulation comprising 2% pilocarpine and 1% Ag1.
  • the duration of the pressure reducing effect of pilocarpine was not extended by the formulation comprising 2% pilocarpine and 1 % Ag 1 as compared to 2% pilocarpine alone.
  • Figures 2, 3a, 3b, 4a and 4b clearly show that the duration of the pressure reducing effect of pilocarpine was extended in the formulations of the present invention incorporating Ag2, an alginate having a guluronic acid percentage of at least 50%.
  • Figure 2 shows intraocular pressure (IOP) before and after treatment with pilocarpine and pilocarpine in combination with 1.5% Ag2, a formulation of the present invention.
  • IOP intraocular pressure
  • Figure 2 depicts the mean baseline values for three rabbits, for pilocarpine (without carrier) and mean baseline values for three rabbits, for the Ag2 formulation without pilocarpine.
  • Figure 2 also depicts the mean values of IOP for three rabbits after treatment with a 2% pilocarpine solution and the formulation of the present invention comprising 2% pilocarpine and 1.5% Ag2.
  • Figures 3a & 3b show intraocular pressure (IOP) before and after treatment with pilocarpine and pilocarpine in combination with Ag2, a formulation of the present invention.
  • IOP intraocular pressure
  • Figure 3a depicts the mean baseline values for six rabbits, for pilocarpine (without carrier) and mean baseline values for six rabbits, for the Ag2 formulation without pilocarpine.
  • Figure 3a also depicts the mean values of IOP for six rabbits after treatment with a 4% pilocarpine solution and the formulation of the present invention comprising 4% pilocarpine and 1.5% Ag2.
  • Figure 3b depicts the mean ⁇ standard error (SE) of the treatment values for the treatment with the 4% pilocarpine solution and the formulation of the present invention comprising 4% pilocarpine and 1.5% Ag2 shown in Figure 3a.
  • SE standard error
  • Figures 4a & 4b show intraocular pressure (IOP) before and after treatment with pilocarpine and pilocarpine in combination with Ag2, a formulation of the present invention.
  • IOP intraocular pressure
  • Figure 4a depicts the mean baseline values for eight rabbits, for pilocarpine (without carrier) and mean baseline values for eight rabbits, for the Ag2 formulation without pilocarpine.
  • Figure 4a also depicts the mean values of IOP for six rabbits after treatment with a 2% pilocarpine solution and the formulation of the present invention comprising 2% pilocarpine and 1% Ag2.
  • Figure 4b depicts the mean ⁇ standard error (SE) of the treatment values for the treatment with the 2% pilocarpine solution and the formulation of the present invention comprising 2% pilocarpine and 1% Ag2 shown in Figure 4a.
  • SE standard error
  • Figures 5a & 5b show intraocular pressure (IOP) before and after treatment with pilocarpine and pilocarpine in combination with Ag3, an alginate having a guluronic acid percentage below that specified for the alginate formulations used in the present invention.
  • Figure 5a depicts the mean baseline values for nineteen rabbits, for pilocarpine (without carrier) and mean baseline values for eight rabbits, for the Ag3 formulation without pilocarpine.
  • Figure 5a also depicts the mean values of IOP for nineteen rabbits after treatment with a 2% pilocarpine solution and the formulation of the present invention comprising 2% pilocarpine and 1% Ag3.
  • Figure 5b depicts the mean ⁇ standard error (SE) of the treatment values for the treatment with the 2% pilocarpine solution and the formulation comprising 2% pilocarpine and 1% Ag3 shown in Figure 5a.
  • SE standard error
  • Figure 6 illustrates the effect of the formulation of the present invention incorporating Ag4, an alginate having a guluronic acid percentage of at least 50%.
  • Figure 6 shows intraocular pressure (IOP) before and after treatment with pilocarpine and pilocarpine in combination with 1.5% Ag4, a formulation of the present invention.
  • IOP intraocular pressure
  • Figure 6 depicts the mean baseline values for six rabbits, for pilocarpine (without carrier) and mean baseline values for six rabbits, for the Ag4 formulation without pilocarpine.
  • Figure 6 also depicts the mean values of IOP for six rabbits after treatment with a 2% pilocarpine solution and the formulation of the present invention comprising 2% pilocarpine and 1.5% Ag4.
  • Figure 7 is a representative graph showing the difference in IOP between pretreatment (baseline) values and the mean values + standard error for eyes treated with 2% pilocarpine alone and a formulation of the present invention incorporating 2% pilocarpine and 1% Ag 2. As shown in Figure 7, the duration of the pressure reducing effect of pilocarpine was extended in eyes treated with the formulation of the present invention incorporating 2% pilocarpine and 1% Ag2, in comparison with the baseline values, and in comparison to treatment with 2% pilocarpine alone.
  • Example 1 The experiment described in Example 1 was repeated using epinephrine in 1% Ag2 (MANUGEL DMB), a formulation of the present invention. The results are depicted graphically in Figure 8.
  • Figure 8 is a representative graph showing the difference in IOP between pretreatment (baseline) values and the mean values ⁇ standard error for eyes treated with 1% epinephrine alone and a formulation of the present invention incorporating 1% epinephrine and 1% Ag 2. As shown in Figure 8, a significant delay and increase in the duration of pressure reduction was observed in eyes treated with the formulation of the present invention incorporating 1% epinephrine and 1% Ag2, in comparison to treatment with 1% epinephrine alone.

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  • Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Claims (12)

  1. Ophthalmische Zubereitung, umfassend:
    eine therapeutisch wirksame Menge zumindest eines Wirkstoffs, und ein Natriumalginat, umfassend zumindest 50 % Guluronsäure, wobei das Natriumalginat bei Kontakt mit Tränenflüssigkeit in eine Gelphase überführt wird.
  2. Ophthalmische Zubereitung nach Anspruch 1, in der das Natriumalginat zumindest 60 % Guluronsäure umfasst.
  3. Ophthalmische Zubereitung, umfassend:
    eine therapeutisch wirksame Menge zumindest eines Wirkstoffs, und
    ein Natriumalginat, dessen Zusammensetzung nicht mehr als 50 % Mannuronsäure umfasst, wobei das Natriumalginat bei Kontakt mit Tränenflüssigkeit in eine Gelphase überführt wird.
  4. Ophthalmische Zubereitung nach Anspruch 3, in der das Natriumalginat nicht mehr als 40 % Mannuronsäure umfasst.
  5. Ophthalmische Zubereitung nach Anspruch 1, in der das Natriumalginat 50 bis 95 % Guluronsäure und 5 bis 50 % Mannuronsäure umfasst.
  6. Ophthalmische Zubereitung nach Anspruch 1, in der zumindest einer der Wirkstoffe ein therapeutisches Mittel für das Auge darstellt.
  7. Ophthalmische Zubereitung nach Anspruch 1, in der der zumindest eine Wirkstoff aus einem Glaukommittel, einem Mittel gegen Entzündung, einem antibakteriellen Mittel, einem Antivirusmittel und einem Mittel gegen Grauen Star ausgewählt wird.
  8. Ophthalmische Zubereitung nach Anspruch 1, in der der zumindest eine Wirkstoff aus einem β-adrenergischen Blocker, einem cholinergen Mittel, einem α-adrenergen Agonisten und einem steroidalen oder einem nicht-steroidalen (NSAID) Mittel gegen Entzündungen ausgewählt wird.
  9. Ophthalmische Zubereitung nach Anspruch 1, in der der zumindest eine Wirkstoff aus Pilocarpin, Acyclovir, Epinephrin, Ciprofloxacin, Natriumchromoglycat, Dexamethason und Timolol ausgewählt wird.
  10. Verwendung von:
    einer therapeutisch wirksamen Menge zumindest eines Wirkstoffs, und
    eines Natriumalginats, umfassend zumindest 50 % Guluronsäure, wobei das Natriumalginat nach Verabreichung auf das Auge und Kontakt mit Tränenflüssigkeit in eine Gelphase überführt wird, zur Herstellung einer ophthalmischen Zubereitung mit kontrollierter Freisetzung für die Behandlung von Augenkrankheiten.
  11. Verwendung nach Anspruch 10, wobei das Natriumalginat zumindest 60 % Guluronsäure umfasst.
  12. Verwendung von:
    einem Natriumalginat, umfassend zumindest 50 % Guluronsäure, wobei das Natriumalginat nach Verabreichung auf das Auge und Kontakt mit Tränenflüssigkeit in eine Gelphase überführt wird, zur Herstellung einer ophthalmischen Zubereitung mit kontrollierter Freisetzung für die Behandlung von Augenkrankheiten.
EP95923983A 1994-06-20 1995-06-19 Ophthalmologisches abgabesystem Expired - Lifetime EP0777451B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US26229494A 1994-06-20 1994-06-20
US262294 1994-06-20
PCT/US1995/007789 WO1995035073A1 (en) 1994-06-20 1995-06-19 Ophthalmic delivery system

Publications (3)

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EP0777451A1 EP0777451A1 (de) 1997-06-11
EP0777451A4 EP0777451A4 (de) 1998-06-10
EP0777451B1 true EP0777451B1 (de) 2001-12-19

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US (1) US5776445A (de)
EP (1) EP0777451B1 (de)
AT (1) ATE210943T1 (de)
DE (1) DE69524772D1 (de)
IL (1) IL114193A (de)
WO (1) WO1995035073A1 (de)

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EP0777451A1 (de) 1997-06-11
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IL114193A0 (en) 1995-10-31
ATE210943T1 (de) 2002-01-15
IL114193A (en) 2000-02-29
WO1995035073A1 (en) 1995-12-28
US5776445A (en) 1998-07-07

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